Chemical biology targeting the brain : Molecular design of anticancer agents that efficiently attack brain tumors

2009 Fiscal Year Final Research Report

• Project/Area Number: 18201041
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Living organism molecular science
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: ISHIKAWA Toshihisa Tokyo Institute of Technology, オミックス基盤研究領域, 客員主管研究員 (60193281)
• Co-Investigator(Renkei-kenkyūsha): SAKURAI Minoru 東京工業大学, バイオ研究基盤支援総合センター, 教授 (50162342) ; DOI Takayuki 東北大学, 大学院・薬学研究科, 教授 (90212076) ; NAKAGAWA Hiroshi 東京工業大学, 生命理工学研究科, 助手 (40397039)
• Project Period (FY): 2006 – 2009
• Keywords: 癌 / 脳・神経 / 生理活性 / 創薬 / 分子プローブ

Research Abstract

The efficacy of cancer chemotherapy in brain tumors is substantially limited by cellular mechanisms where the blood-bran-barrier limits drug penetration into the brain. ATP-binding cassette (ABC) transporters, e.g., ABCB1 and ABCG2, play pivotal roles. In this research project, we have developed high-speed screening and quantitative structure-activity-relationship (QSAR) analysis methods to design anticancer drug molecules that efficiently target brain tumors.

Research Products

• [Journal Article] Key role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis. (2010)
  • Author(s): Ishikawa T, Nakagawa H, Hagiya Y, Nonoguchi N, Miyatake S, Kuroiwa T
  • Journal Title: Adv. Pharm. Sci. (in press)
  • Peer Reviewed
• [Journal Article] Emerging new technologies in pharmacogenomics: Rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1). (2010)
  • Author(s): Ishikawa T., Sakurai A, Hirano H, Lezhava A, Sakurai M, Hayashizaki Y
  • Journal Title: Pharmacol. Ther. 126 Pages: 69-81
  • Peer Reviewed
• [Journal Article] Emerging new technology: QSAR analysis and MO calculation to characterize the interaction of protein kinase inhibitors with human ABC transporter ABCG2 (BCRP). (2010)
  • Author(s): Saito H, An R, Hirano H, Ishikawa T
  • Journal Title: Drug Metab. Pharmacokin. 25 Pages: 72-83
  • Peer Reviewed
• [Journal Article] QSAR analysis and MO calculation to predict drug interactions with human ABC transporter ABCG2. (2010)
  • Author(s): Saito H, Ishikawa T
  • Journal Title: Current Trends Med. Chem. (in press)
  • Peer Reviewed
• [Journal Article] Technical pitfalls and improvements in high-speed screening and QSAR analysis to predict drug-drug interactions of ABC transporter ABCB11 (bile salt export pump). (2009)
  • Author(s): Saito H, Hirano H, Wangsoo Shin, Nakamura R, Osumi M, Ishikawa T
  • Journal Title: AAPS J 11(3) Pages: 581-589
  • Peer Reviewed
• [Journal Article] Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin-dependent kinase inhibitors in vitro. (2009)
  • Author(s): An R, Hagiya Y, Tamura A, Li S, Saito H, Tokushima D, Ishikawa T
  • Journal Title: Pharm Res 26(2) Pages: 449-458
  • Peer Reviewed
• [Journal Article] Nrf2-dependent induction of human ABC transporter ABCG2 and hemeoxygenase-1 in HepG2 cells by photoactivation of porphyrins: Biochemical implications for cancer cell response to photodynamic therapy. (2008)
  • Author(s): Hagiya Y, Adachi T, Ogura S, An R, Tamura A, Nakagawa H, Okura I, Mochizuki T, Ishikawa T
  • Journal Title: J. Exp. Ther. Oncol 7 Pages: 153-167
  • Peer Reviewed
• [Journal Article] Quantitative SAR analysis and molecular dynamic simulation to functionally validate nonsynonymous polymorphisms of human ABC transporter ABCB1. (2007)
  • Author(s): Sakurai A, Onishi Y, Hirano H, Seigneuret M, Obanayama K, Kim G, Liew EL, Sakaeda T, Yoshiura K, Niikawa N, Sakurai M, Ishikawa T
  • Journal Title: Biochemistry 46(26) Pages: 7678-7693
  • Peer Reviewed
• [Journal Article] Theoretical Studies for Molecular Modeling of New Camptothecin Analogues. Croat. (2007)
  • Author(s): Aida-Hyugaji, S., Nakagawa, H., Nomura, J., Sakurai, M., Nagashima, U., Ishikawa, T
  • Journal Title: Chemica. Acta 80(2) Pages: 277-281
  • Peer Reviewed
• [Journal Article] Transport mechanism-based drug molecular design: novel camptothecin analogues to circumvent ABCG2-associated drug resistance of human tumor cells. (2006)
  • Author(s): Ishikawa T, Ikegami Y, Sano K, Nakagawa H, Sawada S
  • Journal Title: Curr. Pharm. Des 12(3) Pages: 313-325
  • Peer Reviewed
• [Journal Article] Molecular modeling of new camptothecin analogues to circumvent ABCG2-mediated drug resistance in cancer. (2006)
  • Author(s): Nakagawa H, Saito H, Ikegami Y, Aida-Hyugaji S, Sawada S, Ishikawa T
  • Journal Title: Cancer Lett 234(1) Pages: 81-89
  • Peer Reviewed
• [Journal Article] High-Speed Screening and QSAR Analysis of Human ATP-Binding Cassette Transporter ABCB11 (Bile Salt Export Pump) To Predict Drug-Induced Intrahepatic Cholestasis. (2006)
  • Author(s): Hirano H, Kurata A, Onishi Y, Sakurai A, Saito H, Nakagawa H, Nagakura M, Tarui S, Kanamori Y, Kitajima M, Ishikawa T
  • Journal Title: Mol. Pharm 3(3) Pages: 252-265
  • Peer Reviewed
• [Journal Article] A new strategy of high-speed screening and quantitative structure-activity relationship analysis to evaluate human ATP-binding cassette transporter ABCG2-drug interactions. (2006)
  • Author(s): Saito H, Hirano H, Nakagawa H, Fukami T, Oosumi K, Murakami K, Kimura H, Kouchi T, Konomi M, Tao E, Tsujikawa N, Tarui S, Nagakura M, Osumi M, Ishikawa T
  • Journal Title: J. Pharmacol. Exp. Ther 317(3) Pages: 1114-1124
  • Peer Reviewed
• [Presentation] QSAR-based prediction and identification of novel dual inhibitors against ABCG2/BCRP and protein kinases (2010)
  • Author(s): Saito, H., Hirano, H., Ishikawa, T
  • Organizer: 3rd FEBS Special Meeting on ABC Proteins
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 2010-03-04
• [Presentation] The impacts of posttranslational modifications and non-synonymous SNPs on the protein stability of human ABC transporter ABCG2 protein in culture cells (2010)
  • Author(s): Nakagawa, H., Wakabayashi-Nakao, K., Tamura, A., Toyoda, Y., Koshiba, S., Furukawa, T., Ishikawa, T.
  • Organizer: 3rd FEBS Special Meeting on ABC Proteins
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 2010-03-04
• [Presentation] N-linked glycosylation stabilizes the de novo synthesized human ABC transporter ABCG2 protein (2009)
  • Author(s): Nakagawa, H., Wakabayashi-Nakao, K., Tamura, A., Ishikawa, T.
  • Organizer: 68th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2009-10-03
• [Presentation] Three-Dimensional SAR analysis of protein kinase inhibitors identified by QSAR analysis of human ABC transporter ABCG2 (2009)
  • Author(s): Saito, H., Nakagawa, H., Ishikawa, T.
  • Organizer: 68th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2009-10-03
• [Presentation] Nrf2-dependent Induction of Human ABC Transporter ABCG2 and Heme oxygenase-1 in HepG2 cells by Photoactivation of Porphirins: Biochemical Implications for Cancer Cell Response to Photodynamic Therapy (2009)
  • Author(s): Hagiya, Y., Adachi, T., Ogura, S., An, R., Tamura, I., Nakagawa, H., Okura, I., Mochizuki, T., Ishikawa, T.
  • Organizer: The 5th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-25
• [Presentation] Identification and Inhibitory Characterization of Protein Kinase Inhibitors Based on QSAR Analysis of Human ABC Transporter ABCG2 (2009)
  • Author(s): Saito, H., Hirano, H., Ishikawa, T.
  • Organizer: The 5th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-25
• [Presentation] Pharmacogenomics and QSAR analysis of human ABC transporter ABCG2 (2008)
  • Author(s): Ishikawa, T.
  • Organizer: SymCYP Seminar
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2008-12-10
• [Presentation] SAR in ABC transporters (2008)
  • Author(s): Ishikawa, T.
  • Organizer: AAPS Annual Meeting
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2008-11-19
• [Presentation] Transporter mechanism-based drug molecular design: High-speed screening, QSAR analysis and molecular orbital calculation (2008)
  • Author(s): Ishikawa, T.
  • Organizer: IPAB/AHeDD Symposium
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2008-10-17
• [Presentation] Basic research and current knowledge on BCRP (2008)
  • Author(s): Ishikawa, T.
  • Organizer: FDA Critical Path Transporter Workshop
  • Place of Presentation: Bethesda, MD, USA
  • Year and Date: 2008-10-02
• [Presentation] Pharmacogenomics of human ABC transporters: functional validation and detection of clinically important SNPs (2008)
  • Author(s): Ishikawa, T.
  • Organizer: National Cancer Institute (NCI), NIH
  • Place of Presentation: Bethesda, MD, USA
  • Year and Date: 2008-09-30
• [Presentation] Human ABC transporter ABCG2: in vitro assay methods for drug molecular design and clinical application of pharmacogenomics (2008)
  • Author(s): Ishikawa, T.
  • Organizer: AstraZeneca Seminar
  • Place of Presentation: Wilmington, USA
  • Year and Date: 2008-09-28
• [Book] MRP1 (ABCC1)「薬物トランスポーター活用ライブラリー機能・輸送基質から創薬・臨床応用まで」(乾賢一・編) (2009)
  • Author(s): 石川智久
  • Total Pages: 136-139
  • Publisher: 羊土社
• [Book] 創薬スクリーニング:発現系の構築から創薬への応用「薬物トランスポーター活用ライブラリー機能・輸送基質から創薬・臨床応用まで」(乾賢一・編) (2009)
  • Author(s): 石川智久
  • Total Pages: 158-163
  • Publisher: 羊土社
• [Book] ポルフィリン(ポルフィリンの光励起によるヒトABCトランスポーターABCG2とヘムオキシゲナーゼの誘導におけるNrf2の役割) (2009)
  • Author(s): 萩谷祐一郎、足立達彦、小倉俊一郎、安然、田村藍、中川大、望月徹、石川智久
  • Total Pages: 12-18
• [Book] プロテインキナーゼとABCトランスポーターを標的とした分子標的医薬の開発とその戦略「バイオ医薬の開発技術とシーズ」山本重夫監修 (2008)
  • Author(s): 齊藤光、石川智久
  • Total Pages: 12-21
  • Publisher: シーエムシー出版
• [Book] 天然物及び食品添加物による細胞内レドックス制御機構の温故知新
  • Author(s): 足立達彦、萩谷祐一郎、中川大、石川智久
  • Total Pages: 214,35-47
  • Publisher: Foods & Food Ingredients Jounal of Japan
• [Patent(Industrial Property Rights)] 抗ガン剤耐性克服剤 (2007)
  • Inventor(s): 平野益治、山川富雄、石川智久、齊藤光
  • Industrial Property Rights Holder: 日本ケミファ株式会社
  • Industrial Property Number: PCT/WO・PCT/WO2007/148835 A1
  • Filing Date: 2007-12-27
• [Patent(Industrial Property Rights)] 化合物の生理活性の定量的予測方法 (2006)
  • Inventor(s): 平野弘之、辻川登、石川智久
  • Industrial Property Rights Holder: 石川智久、辻川登
  • Industrial Property Number: 国内出願・特願2006-167002
  • Filing Date: 2006-06-16
• [Patent(Industrial Property Rights)] 化合物の生理活性の定量的予測方法 (2006)
  • Inventor(s): 平野弘之、辻川登、石川智久
  • Industrial Property Rights Holder: 石川智久、辻川登(すべての指定国)平野弘之(米国のみ)
  • Industrial Property Number: PCT国際出願・PCT/JP2006/313076
  • Filing Date: 2006-06-30
• [Patent(Industrial Property Rights)] 遺伝子多型の検出方法および薬物のスクリーニング方法 (2006)
  • Inventor(s): 石川智久、櫻井亜季、田村藍
  • Industrial Property Rights Holder: 国立大学法人東京工業大学(米国を除く全ての指定国)石川智久、櫻井亜季、田村藍(米国のみ)
  • Industrial Property Number: PCT国際出願・PCT/JP2006/317598
  • Filing Date: 2006-08-30